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A number of inherited neurodegenerative disorders (e.g., Huntingtons's disease and spinal and bulbar muscular atrophy) have been traced to the abnormal repetition of CAG sequences in the coding for particular proteins. These mutant proteins have been tracked into the nuclei of various cells, which is where some researchers suspect they initiate cell death. This suspicion gets support from a report in this month's Nature Genetics, which finds that the mutant proteins produced by the repeats can interfere with gene transcription.

Shoji Tsuji and Takayoshi Shimohata of Niigata University in Japan, along with collaborators from a number of other institutions, hypothesized that interactions between the expanded polyglutamine (polyQ) stretches produced by the CAG repeats and nuclear proteins might underlie cell death. They found (using four separate methods) that the proteins containing the expanded polyQ stretches bound preferentially to TAF(II)130 (a human TATA-binding protein [TBF]-associated factor), a molecule involved in the regulation of transcription. In particular, TAF(II)130 is a cofactor in transcription activated by CREB (cAMP-responsive element binding protein). Upon binding to TAF(II)130, the mutant proteins strongly inhibited CREB-dependent transcription and led to cell death in several in vitro cell systems. This cell death could be reversed by expression of additional TAF(II)130.

Based on this evidence, the authors say, "Suppression of the inhibition of CREB-dependent transcriptional activation caused by expanded polyQ stretches may offer opportunities for the development of new and potent therapeutic strategies of the treatment of CAG-repeat diseases."—Hakon Heimer